PMID- 33434185 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20220110 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 6 IP - 4 DP - 2021 Feb 22 TI - CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3beta axis. LID - 143643 [pii] LID - 10.1172/jci.insight.143643 [doi] LID - e143643 AB - Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen synthase kinase-3beta. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC. FAU - Mohapatra, Pallavi AU - Mohapatra P AD - Institute of Life Sciences, Bhubaneswar, India. AD - Regional Centre for Biotechnology, Faridabad, India. FAU - Shriwas, Omprakash AU - Shriwas O AD - Institute of Life Sciences, Bhubaneswar, India. AD - Manipal Academy of Higher Education, Manipal, India. FAU - Mohanty, Sibasish AU - Mohanty S AD - Institute of Life Sciences, Bhubaneswar, India. AD - Regional Centre for Biotechnology, Faridabad, India. FAU - Ghosh, Arup AU - Ghosh A AD - Institute of Life Sciences, Bhubaneswar, India. FAU - Smita, Shuchi AU - Smita S AD - Institute of Life Sciences, Bhubaneswar, India. FAU - Kaushik, Sandeep Rai AU - Kaushik SR AD - Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. FAU - Arya, Rakesh AU - Arya R AD - Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. FAU - Rath, Rachna AU - Rath R AD - Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India. FAU - Das Majumdar, Saroj Kumar AU - Das Majumdar SK AD - Department of Radiotherapy and. FAU - Muduly, Dillip Kumar AU - Muduly DK AD - Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India. FAU - Raghav, Sunil K AU - Raghav SK AD - Institute of Life Sciences, Bhubaneswar, India. AD - Regional Centre for Biotechnology, Faridabad, India. AD - Manipal Academy of Higher Education, Manipal, India. FAU - Nanda, Ranjan K AU - Nanda RK AD - Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. FAU - Dash, Rupesh AU - Dash R AD - Institute of Life Sciences, Bhubaneswar, India. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210222 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (CMTM6 protein, human) RN - 0 (DNA-Binding Proteins) RN - 0 (MARVEL Domain-Containing Proteins) RN - 0 (Myelin Proteins) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 4.2.1.11 (ENO1 protein, human) RN - EC 4.2.1.11 (Phosphopyruvate Hydratase) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology MH - Apoptosis/drug effects MH - Biomarkers, Tumor/metabolism MH - Carcinoma, Squamous Cell/pathology MH - Cell Death MH - Cell Line, Tumor MH - Cisplatin/*pharmacology MH - DNA-Binding Proteins/*metabolism MH - Drug Resistance, Neoplasm/*drug effects MH - Esophageal Neoplasms/genetics MH - Esophageal Squamous Cell Carcinoma/drug therapy/genetics MH - Gene Expression Regulation, Neoplastic/drug effects MH - Glycogen Synthase Kinase 3 beta/genetics/*metabolism MH - Head and Neck Neoplasms/drug therapy/genetics MH - Humans MH - MARVEL Domain-Containing Proteins MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mouth Neoplasms/drug therapy/pathology MH - Myelin Proteins/genetics/*metabolism MH - Phosphopyruvate Hydratase/metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Squamous Cell Carcinoma of Head and Neck/drug therapy/genetics MH - Tumor Suppressor Proteins/metabolism MH - Up-Regulation/drug effects MH - Wnt Signaling Pathway/*drug effects PMC - PMC7934946 OTO - NOTNLM OT - Cell Biology OT - Head and neck cancer OT - Molecular biology OT - Oncology OT - Signal transduction COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2021/01/13 06:00 MHDA- 2022/01/11 06:00 PMCR- 2021/02/22 CRDT- 2021/01/12 17:19 PHST- 2020/09/08 00:00 [received] PHST- 2021/01/07 00:00 [accepted] PHST- 2021/01/13 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] PHST- 2021/01/12 17:19 [entrez] PHST- 2021/02/22 00:00 [pmc-release] AID - 143643 [pii] AID - 10.1172/jci.insight.143643 [doi] PST - epublish SO - JCI Insight. 2021 Feb 22;6(4):e143643. doi: 10.1172/jci.insight.143643.